Thio-Induced Organophosphate Breakdown Promoted by Methimazole: an Experimental and Theoretical Study.

Investigating the reactivity of small nucleophilic scaffolds is a strategic approach for the design of new catalysts aiming at effective detoxification processes of organophosphorus compounds. The drug methimazole (MMZ) is an interesting candidate featuring two non-equivalent nucleophilic centers. Herein, phosphoryl transfer reactions mediated by MMZ were assessed by means of spectrophotometric kinetic studies, mass spectrometry (MS) analyses, and density functional theory (DFT) calculations using the multi-electrophilic compound O,O-diethyl 2,4-dinitrophenyl phosphate (DEDNPP). MMZ anion acts primarily as an S-nucleophile, exhibiting a nucleophilic activity comparable to that of certain oximes featuring alpha-effect. Selective nucleophilic aromatic substitution was observed, consistent with the DFT prediction of a low energy barrier. Overall, the results bring important advances regarding the mechanistic understanding of nucleophilic dephosphorylation reactions, which comprises a strategic tool for neutralizing toxic organophosphates, hence promoting chemical security.

Quantum Chemistry Calculations for Metabolomics.

A primary goal of metabolomics studies is to fully characterize the small-molecule composition of complex biological and environmental samples. However, despite advances in analytical technologies over the past two decades, the majority of small molecules in complex samples are not readily identifiable due to the immense structural and chemical diversity present within the metabolome. Current gold-standard identification methods rely on reference libraries built using authentic chemical materials ("standards"), which are not available for most molecules. Computational quantum chemistry methods, which can be used to calculate chemical properties that are then measured by analytical platforms, offer an alternative route for building reference libraries, i.e., in silico libraries for "standards-free" identification. In this review, we cover the major roadblocks currently facing metabolomics and discuss applications where quantum chemistry calculations offer a solution. Several successful examples for nuclear magnetic resonance spectroscopy, ion mobility spectrometry, infrared spectroscopy, and mass spectrometry methods are reviewed. Finally, we consider current best practices, sources of error, and provide an outlook for quantum chemistry calculations in metabolomics studies. We expect this review will inspire researchers in the field of small-molecule identification to accelerate adoption of in silico methods for generation of reference libraries and to add quantum chemistry calculations as another tool at their disposal to characterize complex samples.

Competitive Reactivity of Tautomers in the Degradation of Organophosphates by Imidazole Derivatives.

The harmful impact caused by pesticides on human health and the environment necessitates the development of efficient degradation processes and control of prohibited stocks of such substances. Organophosphates (OPs) are among the most used agrochemicals in the world and their degradation can proceed through several possible pathways. Investigating the reactivity of OPs with nucleophilic species allows one to propose new and efficient catalyst scaffolds for use in detoxification. In light of the remarkable catalytic activity of imidazole (IMZ) at promoting dephosphorylation processes of OPs, the reactivity of 4(5)-hydroxymethylimidazole (HMZ) with diethyl-2,4-dinitrophenylphosphate (DEDNPP) and Paraoxon are evaluated by combining experimental and theoretical approaches. It is observed that HMZ is an efficient and regiospecific catalyst with reactivity modulated by competing tautomers. To propose an optimal IMZ-based catalyst, quantum chemical calculations were performed for monosubstituted 4(5)IMZ derivatives that might cleave DEDNPP. Both inductive effects and hydrogen bonding by the substituents are shown to influence barriers and mechanisms.

Coupled Electrocyclization/Prototropic Shift in the Biosynthesis of Crotinsulidane Diterpenoids.

The energetic viability of proposed mechanisms for the formation of the five-membered ring in crotinsulidane diterpenes is assessed using density functional theory calculations. A protonation-assisted coupled four-electron electrocyclization/prototropic shift mechanism is predicted to have a low (biologically relevant) barrier.

The Importance of Methyl Positioning and Tautomeric Equilibria for Imidazole Nucleophilicity.

Imidazole (IMZ) rings catalyze many biological dephosphorylation processes. The methyl positioning effect on IMZs reactivity has long intrigued scientists and its full understanding comprises a promising tool for designing highly efficient IMZ-based catalysts. We evaluated all monosubstituted methylimidazoles (xMEI) in the reaction with diethyl 2,4-dinitrophenyl phosphate by kinetics studies, NMR analysis and DFT calculations. All xMEI showed remarkable rate enhancements, up to 1.9×105 fold, compared with spontaneous hydrolysis. Unexpectedly, the electron-donating methyl group acts to decrease the reactivity of the xMEI compared to IMZ, except for 4(5)methylimidazole, (4(5)MEI). This behavior was attributed to both electronic and steric effects. Moreover, reaction intermediates were monitored by NMR and surprisingly, the reactivity of the two different 4(5)MEI tautomers was distinguished.

The catalytic effect of the NH3 base on the chemical events in the caryolene-forming carbocation cascade.

Caryolene formation occur asynchronously in a concerted way through carbocationic rearrangements involving the generation of a secondary or a tertiary carbocation whether the reaction proceeds in the absence or in the presence of NH3 , respectively. Both caryolene formation mechanisms are analyzed within the general framework of the reaction force; the reaction force constant is used to gain insights into the synchronicity of the mechanisms and the reaction electronic flux helps to characterize the electronic activity taking place during the reaction. DFT calculations at the B3LYP/6-31+G(d,p) level show a clear difference in the mechanisms of the base promoted or base free caryolene formation reactions.

A detailed analysis of the mechanism of a carbocationic triple shift rearrangement.

The mechanism of a carbocationic triple shift rearrangement is analyzed within the conceptual framework of the reaction force. All the systems were characterized computationally using DFT through B3LYP/6-31+G(d,p) methodology. A complete description of the electronic activity taking place during the reaction emerged through the use of the reaction electronic flux that, together with an NBO Wiberg bond order, produces a detailed picture of the reaction mechanism in terms of chemical events that drive the reaction during the different stages of the process. It is found that a carbocation triple shift occurs asynchronously although in a concerted way.

Fusing cubanes to 1,5-hexadiene.

Density functional theory calculations are used to predict structures and reactivity (barriers for sigmatropic shifts and retrocycloadditions) of 1,5-hexadienes fused to cubanes.